title: Increased autophagy in peripheral nerves may protect Wistar Ottawa Karlsburg W rats against neuropathy.
abstract: OBJECTIVE
  Wistar Ottawa Karlsburg W (RT1(u)) rats (WOKW) develop obesity, dyslipidemia, moderate hypertension, hyperinsulinemia and impaired glucose tolerance prone to induce peripheral neuropathy (PN). Autophagy has been shown to prevent neurodegeneration in the central and peripheral nervous system. We analyzed the potential protective role of autophagy in an established rat model in preventing PN.
  
  
  METHODS
  We examined electrophysiology (motor-and sensory/mixed afferent conduction velocities and the minimal F-wave latency) and morphology, including ultrathin sections, myelin sheath thickness (g-ratio) and immunohistochemical markers of autophagy and inflammation in the sciatic nerve of five-month-old, male WOKW as compared to Wistar derived, congenic LEW.1W control rats, characterized by the same major histocompatibility complex as WOKW rats (RT1(u)). Moreover, the expression of axonal and synaptic proteins (NF68, GAP43, MP0), autophagy- (Atg5, Atg7, LC3), and apoptosis (cleaved caspase-3)-related markers was measured using Western blot.
  
  
  RESULTS
  No abnormalities in nerve electrophysiology and morphology were found in WOKW compared to LEW.1W rats. However, autophagosomes were more frequently apparent in sciatic nerves of WOKW rats. In Western blot analyses no significant differences in expression of neuronal structural proteins were found, but autophagy markers were up-regulated in WOKW compared to LEW.1W sciatic nerves. Immunostaining revealed a greater infiltration of Iba1/ED-1-positive macrophages, CD-3-positive T-cells and LC3-expression in sciatic nerves of WOKW rats.
  
  
  CONCLUSIONS
  Our results indicate that WOKW rats show an up-regulated autophagy and a mild inflammatory response but do not develop overt neuropathy. We suggest that autophagy and inflammatory cells may exert a protective role in preventing neuropathy in this rat model of the metabolic syndrome but the mechanism of action is still unclear.
authors.affiliation: Department of Medicine, University of Leipzig, Germany. Electronic address: Joanna.Kosacka@medizin.uni-leipzig.de.
authors.forename: J
authors.initials: J
authors.lastname: Kosacka
authors.forename: M
authors.initials: M
authors.lastname: Nowicki
authors.forename: M
authors.initials: M
authors.lastname: Blüher
authors.forename: P
authors.initials: P
authors.lastname: Baum
authors.forename: M
authors.initials: M
authors.lastname: Stockinger
authors.forename: K V
authors.initials: KV
authors.lastname: Toyka
authors.forename: I
authors.initials: I
authors.lastname: Klöting
authors.forename: M
authors.initials: M
authors.lastname: Stumvoll
authors.forename: H
authors.initials: H
authors.lastname: Serke
authors.forename: I
authors.initials: I
authors.lastname: Bechmann
authors.forename: N
authors.initials: N
authors.lastname: Klöting
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D017933:Peripheral Nervous System / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*
keywords: Atg5; Atg7; Autophagy; CD3; CD68/ED-1; CMAP; CNS; CY3; D; E; FITC; GAP43; GAPDH; HbA1c; IENFD; Iba-1; LC3; LEW.1W; Lewis 1.W; MF; MP0; MS; Metabolic syndrome; NCV; NF200; NF68; PGP9.5; PN; PNS; Peripheral neuropathy; SC; SNAP; Schwann cell; Sciatic nerve; UF; WOKW; WOKW rats; Wistar Ottawa Karlsburg W; autophagy protein 5; autophagy protein 7; central nervous system; cluster of differentiation 3; cluster of differentiation 68; compound muscle action potential; cyanine 3; d-glyceraldehyde-3-phosphate dehydrogenase; dermis; epidermis; fluorescein isothiocyanate; growth associated protein 43; hemoglobin-A1c; intraepidermal nerve fiber density; ionized calcium binding adapter molecule 1; metabolic syndrome; microtubule associated protein light chain 3; myelin protein zero; myelinated fiber; nerve conduction velocity; neurofilament 200; neurofilament 68; peripheral nervous system; peripheral neuropathy; protein gene product 9.5; sensory nerve action potential; unmyelinated fiber